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A Concise and Convergent Synthesis of PA-824 metronidazole (2) is widely used as a general antibacterial
treatment, PA-824 (1) stands out as an exciting experimental
Maurice A. Marsini, Paul J. Reider,* and Erik J. Sorensen* anti-TB drug candidate.5 PA-824 was found to inhibit TB
with minimum inhibitory concentration (MIC) values of
Department of Chemistry, Frick Chemical Laboratory, 0.015-0.25 μg/mL.6 Furthermore, several strains of MDR-
Princeton University, Princeton, New Jersey 08544, TB exhibited comparable susceptibility to PA-824, indicat-
United States ing a lack of potential cross-resistance with current MDR-
TB therapies.7 PA-824 is being developed by the Global
preider@princeton.edu; ejs@princeton.edu Alliance for TB Drug Development (GATB) and is now in
advanced phase II clinical trials.8
Received August 11, 2010
DOI: 10.1021/jo1015807 Published on Web 10/07/2010 J. Org. Chem. 2010, 75, 7479–7482 7479
r 2010 American Chemical Society
JOC Note Marsini et al.
SCHEME 1. Original Production Process for PA-824a SCHEME 2. General Synthetic Strategy
a
DHP = 3,4-dihydropyran; p-TsOH = p-toluenesulfonic acid;
MsOH=methanesulfonic acid.
The original synthesis used to obtain material for clinical SCHEME 3. Synthesis of a Functionalized Glycidol Derivativea
trials provides PA-824 in five linear steps from 2,4-dinitroi-
midazole 4 (Scheme 1).13 Unfortunately, dinitroimidazole 4
is explosive, and both 4 and the starting epoxide 5 are
expensive for use on large scale. Furthermore, the synthesis
requires four chromatographic separations and an inefficient
protection-deprotection sequence in order to selectively
construct the oxazine core that are not suitable for use in a
kilogram-scale process. A solventless modification of this
pathway has also been developed.14
Since the overall cost of any anti-TB drug is a major factor
in future production and necessitates a safe, efficient, and
economic synthesis of this active compound, we set out to
develop a synthesis of PA-824 that would address these
concerns and be amenable to large-scale process develop-
ment (Scheme 2). a
Cl3CCN = trichloroacetonitrile; TBME = tert-butylmethyl ether;
Our key tactical consideration hinges upon the direct, TfOH = trifluoromethanesulfonic acid.
convergent coupling of a suitably safe alternative to
2,4-dinitroimidazole (A) and an appropriately functionalized a removable trigger for our proposed oxazine construction
pseudosymmetrical glycidol derivative (B). Ideally, glycidol because of its stability and migratory resistance.16 To circum-
B would contain the essential p-(trifluoromethoxy)benzyl vent epoxide formation, benzylation of 10 was accomplished
ether moiety with the correct stereochemical configuration under acidic conditions utilizing the benzyltrichloroacetimi-
as well as functional groups to enable either a direct or stepwise date derived from p-(trifluoromethoxy)benzyl alcohol 11 and
construction of the central six-membered oxazine ring. stoichiometric trifluoromethanesulfonic acid in CH2Cl2 at
Our studies began with the synthesis of a suitable glycidol 0 °C in 80% yield. This sequence assembles the desired chloride
derivative (Scheme 3). (R)-3-Chloro-1,2-propanediol (9), 12 in two linear steps from chloride 9 and 60% overall yield.
which is commercially available and easily obtainable from the While the glycidol-derived alkyl chloride 12 was antici-
hydrolytic kinetic resolution (HKR)15 of racemic epichlorohy- pated to be relatively unreactive as an alkylating agent, we
drin on ton-scale, is selectively benzoylated to afford chlor- observed that the desired N-alkylation of 2-chloro-4-nitroi-
ohydrin 10 in 78-82% yield and >99% ee without the need for midazole 13 (CNI)17 could be achieved by the action of
further purification. We chose the p-methoxybenzoyl group as sodium iodide and potassium carbonate on a mixture of 12
and 13 in DMF at 120 °C (Scheme 4). This union was com-
pletely regioselective, most likely due to the bulkiness of the
(12) (a) Li, X.; Manjunatha, U. H.; Goodwin, M. B.; Knox, J. E.; alkylating agent and higher reaction temperature, and af-
Lipinski, C. A.; Keller, T. H.; Barry, C. E.; Dowd, C. S. Bioorg. Med. Chem.
Lett. 2008, 18, 2256–2262. (b) Nagarajan, K.; Shankar, R. G.; Rajappa, S.; forded the desired product 14 in yields ranging from 40%
Shenoy, S. J.; Costa-Pereira, R. Eur. J. Med. Chem. 1989, 24, 631–633. (c) to 50% after recrystallization of the crude reaction mixture.
Matsumoto, M.; Hashizume, H.; Tomishige, T.; Kawasaki, M.; Tsubouchi, This alkylation step offers a significant advantage to the
H.; Sasaki, H.; Shimokawa, Y.; Komatsu, M. PLoS Med. 2006, 3, 2131–
2144. (d) Sutherland, H. S.; Blaser, A.; Kmentova, I.; Franzblau, S. G.; Wan, existing route by circumventing the need for an excess of
B.; Wang, Y.; Ma, Z.; Palmer, B. D.; Denny, W. A.; Thompson, A. M. expensive reagents to obtain the desired regioselectivity.
J. Med. Chem. 2010, 53, 855-866 and references cited therein.
(13) Baker, W. R.; Shaopei, C.; Keeler, E. L. Nitro-[2,1-b]imidazopyran
Compounds and Antibacterial Uses Thereof. U.S. Patent 6,087,358, 2000. (17) (a) 2-Chloro-4-nitroimidazole 13 (CNI) is a non-explosive, crystal-
(14) Orita, A.; Miwa, K.; Uehara, G.; Otera, J. Adv. Synth. Catal. 2007, line compound that is commercially available from Asahi Kasei. For
349, 2136–2144. information concerning the preparation of 2-halo-4-nitroimidazoles and
(15) (a) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N. intermediates thereof, see: Wuellner, G.; Herkenrath, F.-W.; Juelich, A.;
Science 1997, 277, 936–938. (b) Furrow, M. E.; Schaus, S. E.; Jacobsen, E. N. Yamada, Y.; Kawabe, S. PCT Int. Appl. WO 2010021409, August 21, 2009.
J. Org. Chem. 1998, 63, 6776–6777. (b) For an example of the use of this reagent in the synthesis of PA-824
(16) Corey, E. J.; Guzman-Perez, A.; Noe, M. C. J. Am. Chem. Soc. 1995, analogues, please see: Kim, P.; Zhang, L.; Manjunatha, R. S.; Patel, S.;
117, 10805–10816. Jiricek, J.; Barry, C. E.; Dowd, C. S. J. Med. Chem. 2009, 12, 1317–1328.
hexanes); ee >99.9% as determined by chiral SFC (see the Ma from the Global Alliance for TB Drug Development for
Supporting Information); 1H NMR (500 MHz, d6-DMSO) δ their gracious financial support of this research and valuable
8.09 (s, 1H), 7.48 (d, J = 8.6 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H), discussions. We also thank the David Ju Foundation and
4.81-4.62 (m, 3H), 4.51 (d, J = 11.9 Hz, 1H), 4.39-4.19 (m, 3H); Amgen for generous financial support and Dr. Hiromu
13
C NMR (126 MHz, d6-DMSO) δ 148.7, 148.1, 143.0, 138.3, Kawakubo (Asahi Kasei Chemicals Corporation) for a very
130.4, 122.0, 120.0, 119.8, 69.7, 68.8, 67.51, 47.73; IR [CH2Cl2
kind donation of CNI (13) used in these studies.
solution] νmax (cm-1) 2877, 1580, 1543, 1509, 1475, 1404, 1380,
1342, 1281, 1221, 1162, 1116, 1053, 991, 904, 831, 740; HRMS
(ESI-TOF) calcd for C14H12F3N3O5 359.0729, found 359.0728. Supporting Information Available: 1H NMR and 13C NMR
spectra of 1 and 9-14 and chiral SFC data for 10 and 1. This
Acknowledgment. We gratefully acknowledge Dr. material is available free of charge via the Internet at http://
Christopher Cooper, Dr. Takushi Kaneko, and Dr. Zhenkun pubs.acs.org.